Chronic lymphocytic leukemia (CLL)

By Rosemarie Tremblay-LeMay MD FRCPC
March 3, 2022

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What is chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is a type of blood cancer called leukemia. It starts from specialized immune cells called B-lymphocytes that are normally found throughout the body.

What are the symptoms of chronic lymphocytic leukemia?

The symptoms of CLL may be mild, and many patients do not experience any symptoms until later in the disease. For many people, the disease will be discovered during a routine blood test.

Common signs and symptoms of CLL include:

• Swollen lymph nodes that can be felt in the neck, groin, or under the arm;
• Enlarged spleen.
• Fatigue, weight loss, fever, or night sweats.
• Frequent and prolonged infections.
• Increased bruising or bleeding.

People with CLL may develop autoantibodies that cause the immune system to attack their own cells. This can lead to a type of anemia called hemolytic anemia where red blood cells are destroyed. It can also lead to a disease called immune thrombocytopenia, which can result in bruising and bleeding. Many people can also have issues with their immune system that can make them vulnerable to infections.

What is the difference between chronic lymphocytic leukemia and small lymphocytic lymphoma?

When examined under the microscope, the tumour cells in CLL look the same as the tumour cells found in another type of cancer called small lymphocytic lymphoma (SLL). The only real difference between CLL and SLL is where the tumour cells are found. When the tumour cells are found in the blood the disease is called CLL. When the tumour cells are found in lymph nodes and other solid organs but not in the blood the disease is called SLL. Because of these differences, SLL is classified as a type of lymphoma while CLL is classified as a type of leukemia.

Patients that present with CLL can eventually develop SLL, or vice-versa, and patients can present with both at the same time. For that reason, the disease is often described under the name CLL/SLL.

How do pathologists make the diagnosis of chronic lymphocytic leukemia?

The diagnosis of CLL can be made after a blood test or after a small sample of tissue is removed in a procedure called a biopsy. The tissue sample will often be from the bone marrow or an enlarged lymph node.

Your doctor may suspect that you have CLL if your blood test shows an increased number of lymphocytes. Pathologists call this lymphocytosis. If lymphocytosis is found, another test called flow cytometry may be performed on your blood sample. This test allows your pathologist to determine if the lymphocytes are abnormal. See the Flow cytometry section below for more information.

What does chronic lymphocytic leukemia look like under the microscope?

When examined under the microscope, the cancer cells in the blood are small and they have little substance in a part of their cell body called the cytoplasm. The cells are fragile and tend to break when the blood is spread on a glass slide. Pathologists call these broken cells smudge cells.

Instead of being evenly spread out, the genetic material or chromatin in the nucleus of the cell will also appear as small dots. Pathologists describe this look as clumpy and may say that the chromatin looks like a soccer ball (dark dots on a pale background).

What other tests are performed to confirm the diagnosis?

Immunohistochemistry

Your pathologist will perform a test called immunohistochemistry to learn more about the tumour and to exclude other diseases that can look similar to CLL under the microscope. Immunohistochemistry is a test that allows pathologists to see the different types of proteins produced by cells in a tissue sample. When the cells produce a protein, pathologists describe the result as positive or reactive. When the cells do not produce the protein, the result is described as negative or non-reactive.

Because the cancer cells in CLL come from specialized immune cells called B-lymphocytes, they produce proteins normally made by this type of cell. These proteins include CD20, CD19, PAX5, and CD79a. The expression of CD20 is usually weaker than normal, healthy B-lymphocytes. The cancer cells also usually produce CD5, CD23, CD43, and LEF1. CD10 and CyclinD1 are found in other types of B-cell lymphomas and are not produced by the cancer cells in CLL.

Flow cytometry

Flow cytometry is a special test that is used to examine the immune cells in the blood, bone marrow, or tissue samples. Another name for this test is flow immunophenotyping. Unlike other types of laboratory tests, flow cytometry can examine millions of individual cells very quickly and collect information about each cell. The information collected includes the cell size and shape and the types of proteins being made by each cell.

When examined by flow cytometry, the tumour cells in CLL will have strong expression of the protein CD200. Expression of the protein CD38 in more than 30% of the tumour cells can be associated with more aggressive disease.

Molecular tests

Each cell in your body contains a set of instructions that tell the cell how to behave. These instructions are written in a language called DNA and the instructions are stored on 46 chromosomes in each cell. Because the instructions are very long, they are broken up into sections called genes and each gene tells the cell how to produce a piece of the machine called a protein.

Pathologists test for changes involving chromosomes by performing fluorescence in situ hybridization (FISH). When FISH is performed on CLL an abnormal number of chromosomes may be found. The test may also show that a piece of a chromosome has been lost.

The most common changes seen in CLL are:

• Trisomy 12 – The cancer cells have an extra copy of chromosome 12.
• 13q deletion – Part of chromosome 13 is lost.
• 11q23 or ATM – Part of chromosome 11 is lost.
• 17p deletion – Part of chromosome 17 is lost The lost genetic material includes a gene called TP53.

Tumours that have lost part of chromosome 11 or chromosome 17, and those that show complex changes (multiple gains or losses), can behave more aggressively than tumours without these changes.

Some tumours will show a change (a mutation) in a gene called immunoglobulin heavy chain. This gene produces a protein that helps B-cells recognize foreign proteins in the body (such as those on viruses). Tumours with this mutation are less aggressive and may have a more favorable prognosis compared to tumours without the mutation.

What are prolymphocytes and why are they important in chronic lymphocytic leukemia?

A small number of larger lymphocytes called prolymphocytes are also usually seen. These cells usually make up less than 15% of the cancer cells seen in the sample. If the number of prolymphocytes is greater than 15% but is still less than 55%, your pathologist will describe the changes as atypical CLL.

Atypical CLL cells are more likely to have an extra copy of chromosome 12 (trisomy 12) and the cells may produce proteins that are not typically produced by CLL cells. If more than 55% of the cancer cells in the sample are prolymphocytes, the diagnosis changes to B-cell prolymphocytic leukemia, which is a different, more aggressive type of cancer.

The cancer cells seen in a tissue sample such as a lymph node are very similar looking to those seen in the blood. The cancer cells are mostly small, except for groups of larger cells called proliferation centers.

What does transformation mean and why is it important in chronic lymphocytic leukemia?

Over time, CLL can change into a more aggressive type of lymphoma. Pathologists call this a transformation. Your pathologist will carefully examine the sample to look for any evidence of transformation.

CLL can transform in one of three ways:

• Prolymphocytoid transformation.
• Diffuse large B-cell lymphoma.
• Classic Hodgkin lymphoma.

Because these conditions are more aggressive, they require different treatment than CLL without transformation.